Cochlear synaptopathy and hidden hearing loss: a scoping review

Marina de Figueiredo Colla; Pamela Papile Lunardelo; Fernanda Abalen Martins Dias

doi:10.1590/2317-1782/20232023032en

. 2023 Nov 20;36(2):e20230032. doi: 10.1590/2317-1782/20232023032en

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Cochlear synaptopathy and hidden hearing loss: a scoping review

Marina de Figueiredo Colla ^1,^✉, Pamela Papile Lunardelo ², Fernanda Abalen Martins Dias ¹

PMCID: PMC10715634 PMID: 37991055

ABSTRACT

Purpose

To identify the pathophysiological definitions adopted by studies investigating “cochlear synaptopathy” (CS) and “hidden hearing loss” (HHL).

Research strategies

The combination of keywords “Auditory Synaptopathy” or “Neuronal Synaptopathy” or “Hidden Hearing Loss” with “etiology” or “causality” or “diagnosis” was used in the databases EMBASE, Pubmed (MEDLINE), CINAHL (EBSCO), and Web of Science.

Selection criteria

Studies that investigated CS or HHL in humans using behavioral and/or electrophysiological procedures were included.

Data analysis

Data analysis and extraction were performed with regard to terminology, definitions, and population.

Results

49 articles were included. Of these, 61.2% used the CS terminology, 34.7% used both terms, and 4.1% used HHL. The most-studied conditions were exposure to noise and tinnitus.

Conclusion

CS terminology was used in most studies, referring to the pathophysiological process of deafferentiation between the cochlear nerve fibers and inner hair cells.

Keywords: Hearing, Hidden Hearing Loss, Cochlear Synaptopathy, Terminology, Review

INTRODUCTION

Cochlear synaptopathy (CS) is characterized by deafferentiation between cochlear nerve fibers and inner hair cells (IHC) in the spiral ganglion (SG). Cochlear neurons and their vulnerable synaptic connections are the main targets of some pathological agents, with predominant involvement of low spontaneous rates and high-threshold fibers⁽¹⁾. This pathological process is extra-axial and precedes permanent changes in the auditory threshold. Thus, synaptic deterioration occurs even when the IHC remains intact^(2,3).

Over the years, different terminologies have been assigned to the auditory profile characterized by the presence of normal hearing and suprathreshold deficits⁽⁴⁾ because this manifestation may be associated with different diseases that affect the auditory system. Currently, the most common designations for deafferentiation are the CS and Hidden Hearing Loss (HHL).

The main clinical manifestations of CS are difficulty in understanding speech in noisy environments, tinnitus, and hyperacusis in the presence of normal hearing^(3,5-11). However, it should be emphasized that such manifestations are common to several auditory and/or otological pathological processes in addition to CS.

Different factors have been identified as the cause of CS, with exposure to noise and aging being the main factors^{(1,3,4,8,12,13)}. Exposure to high sound pressure levels can cause damage between the synapses of the IHC and the nerve endings of the auditory nerve^(1,14), as it causes excessive release of glutamate in the postsynaptic receptor of the cochlear nerve, promoting excitotoxicity and swelling in the fiber terminals of the SG^(1,15) and initiating a degenerative cascade marked by a temporary increase in the auditory threshold, which is considered transitory⁽¹⁾.

Aging is another possible causal factor. Based on the analysis of the temporal bone in postmortem studies⁽¹⁶⁾, loss of auditory nerve fibers is identified even in the absence of IHC death, or even more pronounced loss of these fibers when there is already cell death. Changes in the auditory threshold only occur when neuronal loss exceeds 80–90%^(2,17). Although this is the “gold standard” procedure to indicate CS, the quantification of cochlear synapses in living humans is not possible⁽¹⁶⁾.

Different non-invasive procedures for assessing the auditory system are used to understand how CS manifests in humans⁽¹⁸⁾. Until now, a decrease in the amplitude of wave I of the Brainstem Auditory Evoked Potential has been assumed to be one of the main findings indicating the presence of CS in individuals with normal hearing and complaints of speech understanding in noise^{(4,7,12,18-20)}. However, other measures have also been widely investigated, such as the potential Frequency Following Response, acoustic stapedial reflex, electrocochleography, and psychoacoustic behavioral tests^(21-24).

While specialized literature has made progress in studying CS, caution must be exercised when suggesting its presence, as it is a specific auditory mechanism disorder, and its main manifestation is also observed in other disorders, including the well-established central auditory processing disorder.

Currently, the synaptic rupture between the IHC strand and the primary auditory neurons is called CS and HHL or even “auditory neuropathy.” Some authors use the term HHL, coined by Schaette and McAlpine⁽³⁾, as a generic term for different auditory disorders that present with normal auditory thresholds. As there is no consensus on the most appropriate terminology and the diagnostic process is still not well defined, diagnosing HHL can be a challenge. One way to contribute to clinical consensus and reduce confusion about idiopathic issues is to identify the terminology adopted in the specialized literature for what is intended to be investigated.

PURPOSE

To identify pathophysiological definitions used by studies that investigated CS and HHL.

Search strategy

This study adopted a comprehensive scope review design following the guidelines recommended by the Joanna Briggs Institute Manual for Evidence Synthesis for Scoping Reviews⁽²⁵⁾ and PRISMA for Scoping Reviews⁽²⁶⁾.

The research question was elaborated using the acronym PCC: population – studies that proposed to investigate CS; concept – the pathophysiological definition attributed to the term used; context –the subjects of these studies ranged from healthy individuals to those with specific conditions or exposures that were considered pathological. The research methodology involved conducting electrophysiological and/or behavioral tests to gather data. The following question was formulated: what pathophysiological definitions have been adopted by studies that investigated CS and/or HHL in humans?

The database was queried between January and February 2022, and a final search was conducted on February 30th. The selected keywords were extracted from PubMed indexing vocabulary, Medical Subject Headings (MeSH Terms), and the Health Sciences Descriptors Library in English. The descriptors were combined as follows: “Auditory Synaptopathy” or “Neuronal Synaptopathy” or “Hidden Hearing Loss” with “etiology” or “causality” or “diagnosis” (Appendix 1). The EMBASE, PubMed (MEDLINE), CINAHL (EBSCO), and Web of Science databases were searched. The study period was from January 1, 2010, to February 28, 2022, to capture relevant research conducted after the term “Hidden Hearing Loss,” coined in 2011 by Schaette and McAlpine ⁽⁽³⁾⁾. Studies focusing on humans and employing various study designs, such as observational studies (including case-control, cohort, and cross-sectional studies) and randomized or uncontrolled clinical trials, were included in the analysis. No language restrictions were applied during selection.

Selection criteria

The selection process was conducted in a blinded and independent manner by two reviewers. Initially, articles were categorized based on their titles and abstracts. Only articles that specifically focused on investigating CS or HHL in human subjects were selected for a more comprehensive evaluation. This evaluation involved carefully reading the articles in full and considering the auditory, behavioral, and/or electrophysiological evaluation procedures used.

Data analysis

Two authors independently analyzed the articles. To facilitate data comprehension, the collected information was categorized into different topics. These categories included: a) author and year of publication, b) type of study, c) target population, d) adopted terminology, and e) pathophysiological definitions. The data were presented descriptively and the analysis was conducted using a descriptive format.

RESULTS

A total of 518 articles were initially identified through the database search (Figure 1). A total of 116 articles were excluded because of duplicity, leaving 402 articles for screening based on their titles and abstracts. From this screening, 52 articles were selected for full reading. During the second selection phase, three articles were excluded because they focused exclusively on postmortem populations. Consequently, 49 articles were selected for further analysis.

Characteristics of the studies

Table 1 provides a chronological overview of the key characteristics of the included studies.

Table 1. Characterization of the articles included in the review.

	Author (Year)	Type of study	Terminology adopted population studied	Definition
1	Schaette et al.⁽³⁾ -2011	Control case	● HHL	“Deafferentiation after noise damage predominantly affects high-threshold NA fibers, while a sufficient number of low-threshold fibers remain responsive to sound.”
1	Schaette et al.⁽³⁾ -2011	Control case	● Tinnitus
2	Mehraei et al.⁽²⁷⁾ -2016	Cross-sectional observational	● CS and HHL - synonyms	“Loss of synapses and cochlear nerve terminals that innervate the IHCs.”
2	Mehraei et al.⁽²⁷⁾ -2016	Cross-sectional observational	● Healthy
3	Bramhall et al.⁽¹⁹⁾ -2017	Control case	● CS	“Partial loss of IHC synapses of auditory nerve fibers.”
3	Bramhall et al.⁽¹⁹⁾ -2017	Control case	● Noise exposure	“Partial loss of IHC synapses of auditory nerve fibers.”
4	Prendergast et al.⁽²⁸⁾ -2017	Cross-sectional observational	● CS and HHL - synonyms	“CS promoted by exposure to noise (often referred to as “HHL”) was demonstrated in a mouse by Kujawa and Liberman (2009).”
4	Prendergast et al.⁽²⁸⁾ -2017	Cross-sectional observational	● Noise exposure
5	Grin et al.⁽²⁹⁾ -2017	Control case	● CS and HHL - synonyms	“A synaptopathic lesion that affects the FMTE, which have higher response thresholds and are responsible for encoding higher-intensity sounds.”
5	Grin et al.⁽²⁹⁾ -2017	Control case	● Noise exposure
6	Paul et al.⁽²¹⁾ -2017	Control case	● CS and HHL - synonyms	“AN fiber damage that does not alter auditory thresholds.”
6	Paul et al.⁽²¹⁾ -2017	Control case	● Tinnitus	“AN fiber damage that does not alter auditory thresholds.”
7	Wojtczak et al.⁽³⁰⁾ -2017	Control case	● CS	“Diffuse and permanent loss between IHC and AN synaptic connections after exposure to high-intensity noise, without measurable permanent changes in cochlear function or auditory sensitivity.”
7	Wojtczak et al.⁽³⁰⁾ -2017	Control case	● Tinnitus
8	Shim et al.⁽³¹⁾ -2017	Control case	● CS and HHL - cause/symptom	“”HHL” is characterized as damage to the AS that is not sufficient to produce a threshold shift,the AS partially recovers as thresholds are restored, despite residual physical damage. Selective loss of high-threshold AN or CS fibers may occur without auditory threshold switching due to intact low-threshold fibers.”
8	Shim et al.⁽³¹⁾ -2017	Control case	● Tinnitus
9	Paul et al.⁽²²⁾ -2017	Cross-sectional observational	● CS	“Damage of the cochlear synapses necessary for supraliminal abilities, even when the cochlear structures necessary for threshold hearing remain unaffected.”
9	Paul et al.⁽²²⁾ -2017	Cross-sectional observational	● Noise exposure
10	Grose et al.⁽⁴⁾ -2017	Control case	● CS	“Suprathreshold deficits in the presence of hearing thresholds within normal limits. In which there is synaptic disruption between the IHC and primary auditory neurons.”
10	Grose et al.⁽⁴⁾ -2017	Control case	● Noise exposure
11	Guest et al.⁽⁵⁾, -2017	Control case	● CS	“Preferential loss of AN fibers with low spontaneous firing rate and high threshold.”
11	Guest et al.⁽⁵⁾, -2017	Control case	● Tinnitus
12	Prendergast et al.⁽³²⁾ -2017	Cross-sectional observational	● CS	“Loss of synapses between IHC and AN fibers.”
12	Prendergast et al.⁽³²⁾ -2017	Cross-sectional observational	● Noise exposure	“Loss of synapses between IHC and AN fibers.”
13	Valderrama et al.⁽³³⁾ -2018	Cross-sectional observational	● CS and HHL - synonyms	“Theory known as “HHL”, in which CS in humans is the hypothesis to explain speech intelligibility deficits in the presence of normal audiogram.”
13	Valderrama et al.⁽³³⁾ -2018	Cross-sectional observational	● Noise exposure
14	Guest et al.⁽³⁴⁾ -2018	Cross-sectional observational	● CS	“Loss of synapses between the IHC and the AN fibers, which can occur without cell loss or permanent threshold elevation.”
14	Guest et al.⁽³⁴⁾ -2018	Cross-sectional observational	● Speech comprehension difficulty
15	Bramhall et al.⁽⁶⁾ -2018	Control case	● CS	“Selective damage to the afferent auditory nerve synapses in the IHC, with auditory thresholds within normal limits.”
15	Bramhall et al.⁽⁶⁾ -2018	Control case	● Noise exposure
16	Guest et al.⁽³⁵⁾ -2019	Cross-sectional observational	● CS	“Loss of synapses between IHC and AN fibers.”
16	Guest et al.⁽³⁵⁾ -2019	Cross-sectional observational	● Tinnitus	“Loss of synapses between IHC and AN fibers.”
17	Ridley et al.⁽³⁶⁾ -2019	Control case	● CS and HHL - cause/symptom	“Damage AN's FBTE and FMTE, which are involved in processing moderate to loud sounds, and are more resistant to masking by background noise. A possible cause for HHL is CS.”
17	Ridley et al.⁽³⁶⁾ -2019	Control case	● SNHL
18	Grose et al.⁽¹²⁾ -2019	Cross-sectional observational	● CS	“Permanent damage to the synapses between the IHC and the AN fibers, insufficient to result in a permanent elevation of auditory thresholds.”
18	Grose et al.⁽¹²⁾ -2019	Cross-sectional observational	● Aging
19	Bhatt & Wang⁽³⁷⁾ -2019	Control case	● CS	“Irreversible damage to the synaptic connections between the IHC and AN. This noise-induced CS cannot be detected by assessing hearing thresholds because noise exposure does not always cause IHC or EHC loss.”
19	Bhatt & Wang⁽³⁷⁾ -2019	Control case	● Noise exposure
20	Johannesen et al.⁽³⁸⁾ -2019	Cross-sectional observational	● CS	“Animal studies have shown that the number of AN fibers decreases with increasing age in healthy cochleae. Some authors speculate that CS and/or deafferentation may be responsible for difficulties in understanding speech in the elderly.”
20	Johannesen et al.⁽³⁸⁾ -2019	Cross-sectional observational	● Healthy
21	Risato-Lago et al.⁽³⁹⁾ -2019	Control case	● HHL	“Condition in which AS damage does not produce threshold change or there is partial recovery as thresholds are restored to original levels despite residual physical damage.”
21	Risato-Lago et al.⁽³⁹⁾ -2019	Control case	● Sickle cell anemia
22	Guest et al.⁽¹⁸⁾ -2019	Control case	● CS	“Loss of synapses between cochlear IHC and AN fibers, without generalized loss of hair cells.”
22	Guest et al.⁽¹⁸⁾ -2019	Control case	● Healthy
23	Prendergast et al.⁽⁴⁰⁾ -2019	Cross-sectional observational	● CS	“Kujawa and Liberman⁽¹⁾ described the phenomenon now known as CS (…) loss of synapses with unchanged absolute thresholds, but associated with a reduction in Wave I..”
23	Prendergast et al.⁽⁴⁰⁾ -2019	Cross-sectional observational	● Noise exposure
24	Megha et al.⁽⁴¹⁾ -2019	Control case	● CS and HHL - synonyms	“Temporary change in the threshold, with damage to the connections between the fibers of the AN and the IHC of the cochlea, causing CS. This type of damage to the synapse, which does not permanently raise the threshold, is called HHL.”
24	Megha et al.⁽⁴¹⁾ -2019	Control case	● Noise exposure
25	Keshishzadeh et al.⁽⁴²⁾ -2020	Control case	● CS	“Irreversible loss of AN synapses and degeneration of cochlear neurons, without damage to cochlear sensory hair cells.”
25	Keshishzadeh et al.⁽⁴²⁾ -2020	Control case	● Speech comprehension difficulty
26	Mepani et al.⁽⁴³⁾ -2020	Cross-sectional observational	● CS	“It is “hidden” because neural degeneration per se does not raise behavioral thresholds or electrophysiological thresholds until it becomes extreme.”
26	Mepani et al.⁽⁴³⁾ -2020	Cross-sectional observational	● Healthy
27	Couth et al.⁽⁴⁴⁾ -2020	Control case	● CS and HHL - synonyms	“Loss of synapses between IHC and spiral ganglion neurons.”
27	Couth et al.⁽⁴⁴⁾ -2020	Control case	● Noise exposure	“Loss of synapses between IHC and spiral ganglion neurons.”
28	Parker et al.⁽¹⁰⁾ -2020	Cross-sectional observational	● CS and HHL - cause/symptom	“Loss of the synaptic connection between the IHC and the AN fibers, impairing the ability to understand in adverse listening situations.”
28	Parker et al.⁽¹⁰⁾ -2020	Cross-sectional observational	● Healthy
29	Grant et al.⁽⁹⁾ -2020	Cross-sectional observational	● CS	“Damage of synapses between cochlear and IHC nerve fibers even as hair cells and thresholds recover.”
29	Grant et al.⁽⁹⁾ -2020	Cross-sectional observational	● Healthy
30	Kara et al.⁽⁴⁵⁾ -2020	Control case	● CS and HHL - synonyms	“Loss of IHC synapses without any evidence of increased auditory thresholds.”
30	Kara et al.⁽⁴⁵⁾ -2020	Control case	● Tinnitus
31	Bramhall et al.⁽⁸⁾ -2020	Control case	● CS	“Loss of synaptic connections between the IHC and their auditory afferent nerve fiber targets.”
31	Bramhall et al.⁽⁸⁾ -2020	Control case	● Tinnitus and noise exposure
32	Shehorn et al.⁽⁴⁶⁾ -2020	Control case	● CS	“Loss of connections between the IHC and the auditory nerve fibers, in the absence of permanent threshold change.”
32	Shehorn et al.⁽⁴⁶⁾ -2020	Control case	● Speech comprehension difficulty
33	Okada et al.⁽⁴⁷⁾, -2020	Cross-sectional observational	● CS	“Reduced cochlear efferent innervation and a loss of afferent synapses between the AN and sensory cells.”
33	Okada et al.⁽⁴⁷⁾, -2020	Cross-sectional observational	● CHL
34	Washnik et al.⁽⁴⁸⁾ -2020	Control case	● CS and HHL - synonyms	“Irreversible damage to the synaptic connections between the cochlear IHC and the NA fibers. This type of peripheral hearing loss can lead to impaired speech perception and has been called “HHL”.
34	Washnik et al.⁽⁴⁸⁾ -2020	Control case	● Noise exposure
35	Carcagno & Plack⁽⁴⁹⁾ -2020	Cross-sectional observational	● CS	“Permanent loss of synapses between IHC and AN fibers.”
35	Carcagno & Plack⁽⁴⁹⁾ -2020	Cross-sectional observational	● Aging	“Permanent loss of synapses between IHC and AN fibers.”
36	Marmel et al.⁽⁵⁰⁾ -2020	Control case	● CS and HHL - synonyms	“Subclinical auditory pathology that could explain some hearing difficulties observed despite (almost) normal audiometric thresholds.”
36	Marmel et al.⁽⁵⁰⁾ -2020	Control case	● Tinnitus
37	Carcagno & Plack⁽⁵¹⁾ -2021	Cross-sectional observational	● CS	“Permanent loss of synapses between IHC and AN fibers.”
37	Carcagno & Plack⁽⁵¹⁾ -2021	Cross-sectional observational	● Aging	“Permanent loss of synapses between IHC and AN fibers.”
38	Shim et al.⁽⁵²⁾ -2021	Control case	● CS	“The selective loss of high-threshold fibers and/or high-threshold synaptopathy.”
38	Shim et al.⁽⁵²⁾ -2021	Control case	● Unilateral tinnitus
39	Bal et al.⁽¹¹⁾ -2021	Control case	● CS and HHL - synonyms	“Damage to cochlear nerve fibers, especially in the FBTE, with disruption of synaptic communication between the sensory IHC and cochlear nerve fiber subsets.”
39	Bal et al.⁽¹¹⁾ -2021	Control case	● Noise exposure
40	Suresh et al.⁽²⁰⁾ -2021	Control case	● CS and HHL - cause/symptom	“Reduction in the number of synaptic strands between the IHC and the AN fibers without affecting the audiometric thresholds.”
40	Suresh et al.⁽²⁰⁾ -2021	Control case	● Noise exposure
41	Nam et al.⁽⁵³⁾ -2021	Control case	● CS and HHL - synonyms	“When synapses are damaged, nerve fibers subsequently degenerate.”
41	Nam et al.⁽⁵³⁾ -2021	Control case	● Noise exposure
42	Megha et al.⁽¹³⁾ -2021	Control case	● SC and HHL - synonyms	“Loss of synapses and cochlear nerve endings that innervate the IHC.”
42	Megha et al.⁽¹³⁾ -2021	Control case	● Noise exposure and aging
43	Wang et al.⁽⁷⁾ -2021	Cross-sectional observational	● CS	“Permanent dysfunction at the junctions between the IHC and the AN fibers caused by low-grade trauma to the inner ear, typically associated with noise exposure, insufficient for permanent elevation of thresholds.”
43	Wang et al.⁽⁷⁾ -2021	Cross-sectional observational	● Noise exposure
44	Vasilkov et al.⁽⁵⁴⁾ -2021	Control case	● CS	“Degeneration of the synaptic terminals of spiral ganglion cells, which precedes IHC damage in the aging process.”
44	Vasilkov et al.⁽⁵⁴⁾ -2021	Control case	● Aging
45	Bramhall et al.⁽²³⁾ -2021	Control case	● CS	“Loss of connection between the IHI and their afferent AN fiber targets.”
45	Bramhall et al.⁽²³⁾ -2021	Control case	● Noise exposure
46	Chen et al.⁽⁵⁵⁾ -2021	Cross-sectional observational	● CS	“Affects the connection between the IHCs, with dysfunction in the FBTE, reducing the ability to perceive speech in a noisy environment.”
46	Chen et al.⁽⁵⁵⁾ -2021	Cross-sectional observational	● Aging
47	Edvall et al.⁽⁵⁶⁾ -2022	Control case	● CS	“Loss of synaptic connection between the IHC and the afferent fibers of the AN.”
47	Edvall et al.⁽⁵⁶⁾ -2022	Control case	● Tinnitus
48	Turner et al.⁽⁵⁷⁾ -2022	Control case	● CS	“Synaptic change between the IHC and the auditory nerve fibers.”
48	Turner et al.⁽⁵⁷⁾ -2022	Control case	● Tinnitus
49	Bramhall et al.⁽²⁴⁾ -2022	Control case	● CS	“Loss of synapses between the IHC and afferent auditory nerve fibers.”
49	Bramhall et al.⁽²⁴⁾ -2022	Control case	● Noise exposure

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Caption: CS = Cochlear synaptopathy; HHL = Hidden Hearing Loss; AN = Auditory Nerve; IHC = Inner Hair Cell; FMTE = Medium Rate Spontaneous Fibers; FBTE = Low Rate Spontaneous Fibers; AS = Auditory System; EHC = External Hair Cell; . SNHL = Sensorineural Hearing Loss; CHL = Conductive Hearing Loss

In terms of study design, the analysis revealed that the majority of the studies 31 (63.2%) were case-control studies, while 36.7% (18 of 49) were cross-sectional observational studies.

Terminology used and its application

Out of the 49 articles included in the study, a majority of them, 61.2% (30/49), utilized the terminology “CS” to refer to the specific phenomenon that has been researched. A smaller proportion of articles, 4.1% (2/49), solely employed the term “HHL.” A significant proportion of the selected articles (34.7%, 17/49) adopted both terms.

Of the articles that adopted CS terminology (Studies 3, 7, 10, 11, 12, 14, 15, 16, 18, 19, 20, 21, 22, 23, 25, 26, 29, 31, 32, 33, 35, 37, 43, 44, 45, 46, 47, 48, and 49), the most commonly used definitions were those of Kujawa and Liberman⁽¹⁾, Makary et al.⁽⁵⁸⁾, Sergeyenko et al.⁽⁵⁹⁾, and Liberman and Kujawa⁽⁶⁰⁾. According to the definitions adopted in these articles, CS is the loss of synapses between the IHC and fibers of the auditory nerve, which produces lesions in fibers with a low rate of spontaneous discharge and a high threshold in the absence of permanent alteration of the auditory threshold⁽¹⁾. A reduction in cochlear efferent innervation and loss of afferent synapses between the cochlear nerve and sensory cells has also been reported^(59,60). These authors agree that CS has been demonstrated in studies on animals, rodents, and primates, mainly as a consequence of exposure to high levels of sound intensity^(1,27-29). Due to the impairment of synapses with efferent fibers, there is an impairment in acoustic stimulus encoding, since it initiates auditory input in the central auditory system. Therefore, it can be inferred that studies using CS terminology aimed to study a phenomenon restricted to a specific location of injury or auditory mechanisms. Furthermore, there are no differences between authors regarding its definition^(1,58-60).

The term “HHL” was used in two studies (Studies 1 and 21). Among the articles that adopted it to designate the objective of the study, one described it as a condition in which there is an alteration in the auditory system without any change in the auditory threshold (Study 21). Thus, the authors considered HHL to be a sign of hearing disease and not the cause itself. In another article (Study 1), HHL was described as deafferentiation between the cochlear nerve fibers and the SG, in which the auditory thresholds remained within normal limits and there was impaired function of efferent fibers that projected from the brainstem to the cochlea.

The terms CS and HHL were adopted together in studies 2, 4, 5, 6, 8, 13, 17, 24, 27, 28, 30, 34, 36, 39, 40, 41, and 42. Of the 17 articles, 76.5% (13/17) assumed HHL to be a synonym for CS (Studies 2, 4, 5, 6, 13, 24, 27, 30, 34, 36, 39, 41, and 42) using the definitions by Schaette et al.⁽³⁾, Kuwaja and Liberman⁽¹⁾. Meanwhile, 23.5% (04/17) differentiated them on the pathological phenomenon and its signs (Studies 8, 17, 28, and 40). In other words, the authors assumed that CS was a possible cause of HHL.

The term HHL is used as a generic designation for at least 14 diseases that affect the auditory system and cause complaints of speech understanding in the absence of peripheral hearing loss. This term is widely accepted for different pathophysiological descriptions, as long as there are no changes in the auditory threshold. Therefore, caution is required when associating it as a synonym for CS, which is characterized in a very specific manner, especially regarding its pathophysiological processes.

It is still necessary to add that, during the search for articles, in two of the selected articles, the use of the term “auditory neuropathy spectrum disorder” was observed, referring to cochlear deafferentiation. Auditory neuropathy is a well-established condition in which cranial nerve VIII is compromised due to changes in neural synchrony during synaptic transmission. The location of the auditory nerve involvement is variable, and there may be peripheral hearing loss of different degrees, unilateral or bilateral, symmetrical, or asymmetrical. Therefore, auditory neuropathy differs from CS⁽⁶¹⁾.

Study Populations

The selected studies included different populations and conditions. The population exposed to high sound pressure levels was the research objective of 44.8% (22/49) of the studies, followed by the population with uni- or bi-lateral tinnitus in 24.4% (12/49), 12.2% (06/49), respectively in the aging condition and 10.2% (05/49) in the “healthy” condition. Conductive hearing loss, sensorineural hearing loss, and sickle cell anemia accounted for 2.0% (01/49) of the studies. Three articles studied more than one condition, two addressed exposure to high levels of sound pressure and tinnitus, and one studied exposure to high levels of sound pressure and aging.

Most of the conditions addressed by these studies were identified as risk factors for CS (e.g. exposure to noise, aging, and tinnitus). Exposure to high sound pressure levels has been the most studied (Studies 3, 4, 5, 6, 10, 12, 13, 15, 16, 19, 23, 24, 27, 31, 34, 39, 40, 41, 42, 43, 45, and 49), possibly because it presents mechanisms of physiological damage that are known and relatively amenable to control CS. However, it is the most likely etiological factor in this pathology. The second most investigated condition was tinnitus (Studies 1, 7, 8, 9, 11, 13, 30, 31, 36, 38, 47, and 48), which is also an indication of CS. However, some considerations regarding this condition are necessary, as it is a heterogeneous symptom in etiology, location, acoustic characteristics, and associated comorbidities⁽⁶²⁾. Tinnitus is often associated with hearing loss, acoustic trauma, exposure to high levels of sound pressure, use of ototoxic drugs, cardiovascular alterations, temporomandibular disorders, or the absence of apparent causes⁽³¹⁾. Thus, to infer that tinnitus was caused by CS, other factors must be excluded. The tinnitus studies included in this review did not mention excluding or documenting the presence of other conditions in their samples, except for hearing loss. The same occurs for aging (Studies 18, 35, 37, 42, 44, and 46), “healthy” conditions (Studies 2, 20, 22, 26, 28, and 29), and speech comprehension complaints (14, 25, 32). To confirm the presence of CS in these populations, it is necessary to exclude changes in the central nervous system, because they also promote changes in suprathreshold abilities⁽⁶³⁾.

Conditions of conductive hearing loss (Study 33), sensorineural hearing loss (Study 17), and sickle cell anemia (Study 21) were also found in the present study. A study that investigated individuals with conductive hearing loss used the term CS. However, this study indicates that chronic conductive hearing loss in adults may be a risk factor for the development of CS. The study on sensorineural hearing loss used the terms CS and HHL as synonyms and was applicable to the studied conditions. However, there was no alteration in the auditory threshold of synaptopathy⁽¹⁾; thus, the designation of what was being investigated may have been mistaken. Finally, the study of individuals with sickle cell anemia used the term HHL only generically to indicate alterations in the auditory system that did not affect the audiogram results.

CONCLUSION

CS terminology was the most commonly used by the included studies, all of which referred to the pathophysiological process of deafferentiation between the cochlear nerve fibers and IHC. Most studies that adopted both terms used them synonymously, whereas others described HHL as a possible consequence of CS. A smaller proportion of the studies solely used the term HHL, considering it as an indication of hearing impairment.

Appendix 1. Search strategy used according to the database

Data base	Search Strategy
PUBMED	((“Auditory Synaptopathy”[All Fields] OR ((“neuron s”[All Fields] OR “neuronal”[All Fields] OR “neuronally”[All Fields] OR “neuronals”[All Fields] OR “neurone s”[All Fields] OR “neurones”[All Fields] OR “neuronic”[All Fields] OR “neurons”[MeSH Terms] OR “neurons”[All Fields] OR “neuron”[All Fields] OR “neurone”[All Fields]) AND (“synaptopathies”[All Fields] OR “synaptopathy”[All Fields])) OR “Hidden Hearing Loss”[All Fields]) AND “etiology”[All Fields]) OR “causality”[All Fields] OR “diagnosis”[All Fields].
EMBASE	('auditory synaptopathy'/exp OR 'auditory synaptopathy' OR 'neuronal synaptopathy' OR 'hidden hearing loss'/exp OR 'hidden hearing loss') AND ('etiology'/exp OR 'etiology') OR 'causality'/exp OR 'causality' OR 'diagnosis'/exp OR 'diagnosis'
CINAHL	Auditory Synaptopathy” OR “Neuronal Synaptopathy” OR “Hidden Hearing Loss” AND etiology OR causality OR diagnosis.
Web of Science	“Auditory Synaptopathy” (All Fields) OR “Neuronal Synaptopathy” (All Fields) OR “Hidden Hearing Loss” (All Fields) AND etiology (All Fields) OR causality (All Fields) OR diagnosis (All Fields).

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Footnotes

Study conducted at Pontifícia Universidade Católica de Minas Gerais – PUC MG - Belo Horizonte (MG), Brasil.

Financial support: nothing to declare.

REFERENCES

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Codas. 2023 Nov 20;36(2):e20230032. [Article in Portuguese] doi: 10.1590/2317-1782/20232023032pt

Sinaptopatia coclear e perda auditiva oculta: uma revisão de escopo

Marina de Figueiredo Colla ^1,^✉, Pamela Papile Lunardelo ², Fernanda Abalen Martins Dias ¹

RESUMO

Objetivo

Identificar as definições fisiopatológicas adotadas pelos estudos que investigaram a “sinaptopatia coclear” (SC) e “perda auditiva oculta” (PAO).

Estratégia de pesquisa

Utilizou-se a combinação de unitermos “Auditory Synaptopathy” or “Neuronal Synaptopathy” or “Hidden Hearing Loss” com “etiology” or “causality” or “diagnosis” nas bases de dados EMBASE, Pubmed (MEDLINE), CINAHL (EBSCO) e Web of Science.

Critérios de seleção

Incluiu-se estudos que investigaram a SC ou PAO em humanos com procedimentos comportamentais e/ou eletrofisiológicos.

Análise dos dados

Realizou-se a análise e extração de dados quanto a terminologia, definição e população estudada.

Resultados

Foram incluídos 49 artigos. Destes, 61,2% utilizaram a terminologia SC, 34,7% ambos os termos e 4,1% utilizaram PAO. As condições mais estudadas foram exposição ao ruído e zumbido.

Conclusão

A terminologia SC foi empregada na maioria dos estudos, com referência ao processo fisiopatológico de desaferenciação entre as fibras do nervo coclear e as células ciliadas internas

Keywords: Audição, Perda Auditiva Oculta, Sinaptopatia Coclear, Terminologia

INTRODUÇÃO

A sinaptopatia coclear (SC) é caracterizada pela desaferenciação entre as fibras do nervo coclear e as células ciliadas internas (CCI) no gânglio espiral (GE). Os neurônios cocleares e suas vulneráveis conexões sinápticas são os principais alvos de alguns agentes patológicos, com acometimento predominante de fibras de baixa taxa espontânea e alto limiar⁽¹⁾. Este processo patológico é extra-axial e precede a mudança permanente do limiar auditivo, desta forma, a deterioração sináptica ocorre mesmo quando as CCI permanecem íntegras^(2,3).

Ao longo dos anos, diferentes nomenclaturas foram atribuídas ao perfil auditivo caracterizado pela presença de audição normal e déficits supraliminares⁽⁴⁾, isto porque, esta manifestação pode estar associada a diferentes doenças que acometem o sistema auditivo. Atualmente, as designações mais comuns atribuídas a desaferenciação supracitada são SC ou perda auditiva oculta (PAO).

As principais manifestações clínicas da SC são a dificuldade de compreensão de fala no ruído, zumbido e hiperacusia na presença de audição normal^(3,5-11). Entretanto, deve-se ressaltar que tais manifestações são comuns a variados processos patológicos auditivos e/ou otológicos e não apenas à SC.

Diferentes fatores são apontados como causa da SC, sendo a exposição ao ruído e o envelhecimento os principais deles^{(1,3,4,8,12,13)}. A exposição a níveis de pressão sonora elevados pode gerar danos entre as sinapses das CCI e as terminações nervosas do nervo auditivo^(1,14), pois ocasiona liberação excessiva de glutamato no receptor pós-sináptico do nervo coclear, promovendo excitotoxicidade e inchaço nas fibras terminais do GE^(1,15), iniciando uma cascata degenerativa, marcada pela elevação temporária do limiar auditivo, considerada transitória⁽¹⁾.

Outro possível fator causal é o envelhecimento. A partir da análise do osso temporal em estudos post-mortem ⁽¹⁶⁾ identifica-se a perda de fibras do nervo auditivo mesmo na ausência de morte das CCI, ou ainda, perda mais acentuada destas fibras quando já existe morte celular. As mudanças no limiar auditivo ocorrem apenas quando a perda neuronal excede cerca de 80% a 90%^(2,17). Embora este seja o procedimento “padrão ouro” para indicar a SC, a quantificação de sinapses cocleares em humanos vivos não é uma medida possível⁽¹⁶⁾.

Diferentes procedimentos não invasivos de avaliação do sistema auditivo são utilizados para compreender como a SC se manifesta em humanos⁽¹⁸⁾. Até o presente momento, assume-se a diminuição da amplitude da onda I do Potencial Evocado Auditivo de Tronco Encefálico (PEATE) como um dos principais achados que poderia indicar a presença de SC em indivíduos com audição normal e queixa de compreensão de fala no ruído^{(4,7,12,18-20)}. Entretanto, outras medidas também são amplamente investigadas, como o potencial Frequency Following Response, o reflexo acústico do músculo da orelha média, a eletrococleografia e alguns testes comportamentais psicoacústicos^(21-24).

Ainda que a literatura especializada tenha avançado nos estudos sobre a SC, é necessário ter cautela ao indicar a possibilidade de sua presença, pois se trata de uma lesão em um mecanismo auditivo muito específico e a sua principal manifestação, também está presente em outros transtornos, o que inclui o já bem estabelecido transtorno do processamento auditivo central.

Atualmente, a ruptura sináptica entre a fita das CCI e os neurônios auditivos primários é denominada de SC e PAO ou até mesmo de “neuropatia auditiva”. Alguns autores apontam o termo PAO, cunhado por Schaette e McAlpine⁽³⁾, como genérico para se referir a diferentes disfunções auditivas com presença de limiares auditivos dentro da normalidade. A falta de consenso quanto ao termo mais adequado pode dificultar o processo de diagnóstico desta patologia que ainda não está bem definida, tornando-se uma problemática. Uma das formas de contribuir para o consenso clínico e reduzir a confusão entre questões idiopáticas, é identificar qual a terminologia adotada na literatura especializada para o que se pretende investigar.

OBJETIVO

Identificar as definições fisiopatológicas adotadas pelos estudos que investigaram a SC e a PAO.

Estratégia de pesquisa

O presente estudo baseou-se no delineamento de revisão de escopo a partir das recomendações da Joanna Briggs Institute Manual for Evidence Synthesis for Scoping Reviews ⁽²⁵⁾ e do PRISMA for Scoping Reviews ⁽²⁶⁾.

A pergunta de pesquisa foi elaborada utilizando-se a sigla PCC: POPULAÇÃO - estudos que se propuseram a investigar a SC e/ou a PAO; Conceito – a definição fisiopatológica atribuída ao termo utilizado; Contexto – estudos com humanos, hígidos ou com alguma condição ou exposição considerada patológica, com testes eletrofisiológicos e/ou comportamentais. Formulou-se a pergunta: Quais definições fisiopatológicas adotadas pelos estudos que propuseram a investigação da SC e/ou da PAO em humanos?

O período de busca nas bases de dados correspondeu aos meses de janeiro e fevereiro de 2022, sendo a data da última busca o dia 30 de fevereiro. Os unitermos selecionados foram extraídos do vocabulário de indexação da PubMed, Medical Subject Headings (MeSH Terms) e na biblioteca de Descritores em Ciência da Saúde (DeCS), no idioma inglês. Os descritores foram combinados da seguinte forma: “Auditory Synaptopathy” or “Neuronal Synaptopathy” or “Hidden Hearing Loss” com “etiology” or “causality” or “diagnosis” (Apêndice 1). As bases de dados pesquisadas foram a EMBASE, Pubmed (MEDLINE), CINAHL (EBSCO) e Web of Science. Estipulou-se como filtro o período de 01 de janeiro de 2010 até 30 de fevereiro de 2022 devido ao termo “Hidden Hearing Loss” ter sido cunhado apenas em 2011 por Schaette e McAlpine⁽³⁾. Ainda, selecionou-se estudos em humanos e o tipo do estudo (estudos observacionais – caso-controle, coortes, transversais – e ensaio clínico randomizado ou não controlado), sem restrições de idioma.

Critérios de seleção

A seleção dos estudos foi realizada de forma cega e independente, por dois revisores. Os artigos foram triados a partir de seu título e resumo, sendo selecionados para leitura na íntegra aqueles que objetivaram investigar a SC ou PAO em humanos por meio de procedimentos de avaliação do sistema auditivo, comportamentais e/ou eletrofisiológicos.

Análise dos dados

A análise dos artigos foi conduzida de forma independente por dois autores. As informações coletadas foram divididas em diferentes tópicos, a fim de possibilitar a compreensão dos dados coletados: a) autor e ano da publicação; b) tipo de estudo; c) população alvo; d) terminologia adotada; e) definição fisiopatológica.

Os dados estão apresentados de forma descritiva e a análise realizada no formato descritivo.

RESULTADOS

A partir da busca nas bases de dados foram identificados inicialmente 518 artigos como apresentados na Figura 1, dos quais 116 foram excluídos por duplicidade. Foram triados pelo título e resumo 402 artigos e selecionados para leitura na íntegra 52. Durante a segunda fase de seleção, três artigos foram excluídos por incluírem apenas a população post-mortem, com isto, foram selecionados para análise 49 artigos.

Características dos estudos

A Tabela 1 apresenta as características dos estudos incluídos, em ordem cronológica de publicação.

Tabela 1. Caracterização dos artigos incluídos na revisão.

	Autor (Ano)	Tipo do estudo	Terminologia adotada	Definição
	Autor (Ano)	Tipo do estudo	população estudada	Definição
1	Schaette et al.⁽³⁾ -2011	Caso controle	● PAO	“Desaferenciação após dano por ruído, afetando predominantemente as fibras do NA de alto limiar, enquanto um número suficiente de fibras de baixo limiar permanece responsivo ao som.”
1	Schaette et al.⁽³⁾ -2011	Caso controle	● Zumbido
2	Mehraei et al.⁽²⁷⁾ -2016	Observacional transversal	● SC e PAO - sinônimos	“Perda das sinapses e de terminais do nervo coclear que inervam as CCI.”
2	Mehraei et al.⁽²⁷⁾ -2016	Observacional transversal	● Hígidos
3	Bramhall et al.⁽¹⁹⁾ -2017	Caso controle	● SC	“Perda parcial das sinapses das CCI das fibras nervosas auditivas.”
3	Bramhall et al.⁽¹⁹⁾ -2017	Caso controle	● Exposição ao ruído
4	Prendergast et al.⁽²⁸⁾ -2017	Observacional transversal	● SC e PAO - sinônimos	“A SC promovida pela exposição ao ruído (muitas vezes referida como “PAO”) foi demonstrada em um camundongo por Kujawa e Liberman (2009).”
4	Prendergast et al.⁽²⁸⁾ -2017	Observacional transversal	● Exposição ao ruído
5	Grin et al.⁽²⁹⁾ -2017	Caso controle	● SC e PAO - sinônimos	“Lesão sinaptopática que acomete as FMTE, que têm limiares de resposta mais altos e são responsáveis por codificar sons de maior intensidade.”
5	Grin et al.⁽²⁹⁾ -2017	Caso controle	● Exposição ao ruído
6	Paul et al.⁽²¹⁾ -2017	Caso controle	● SC e PAO - sinônimos	“Danos nas fibras do NA que não alteram os limiares auditivos.”
6	Paul et al.⁽²¹⁾ -2017	Caso controle	● Zumbido
7	Wojtczak et al.⁽³⁰⁾ -2017	Caso controle	● SC	“Perda difusa e permanente entre as conexões sinápticas das CCI e do NA após a exposição ao ruído de forte intensidade, sem alterações permanentes mensuráveis na função coclear ou sensibilidade auditiva.”
7	Wojtczak et al.⁽³⁰⁾ -2017	Caso controle	● Zumbido
8	Shim et al.⁽³¹⁾ -2017	Caso controle	● SC e PAO - causa/sintoma	“A “PAO” caracteriza-se como um dano ao SA que não é suficiente para produzir uma mudança de limiar, o SA se recupera parcialmente a medida em que os limiares são restaurados, apesar do dano físico residual. A perda seletiva de fibras do NA de alto limiar ou SC pode ocorrer sem alteração do limiar auditivo devido às fibras de baixo limiar intactas.”
8	Shim et al.⁽³¹⁾ -2017	Caso controle	● Zumbido
9	Paul et al.⁽²²⁾ -2017	Observacional transversal	● SC	“Dano das sinapses cocleares necessárias para as habilidades supraliminares, mesmo quando as estruturas cocleares necessárias para a detecção auditiva permanecem inalteradas.”
9	Paul et al.⁽²²⁾ -2017	Observacional transversal	● Exposição ao ruído
10	Grose et al.⁽⁴⁾ -2017	Caso controle	● SC	“Déficits supralimiares na presença limiares auditivos dentro dos padrões de normalidade. Em que existe a ruptura sináptica entre as CCI e os neurônios auditivos primários.”
10	Grose et al.⁽⁴⁾ -2017	Caso controle	● Exposição ao ruído
11	Guest et al.⁽⁵⁾, -2017	Caso controle	● SC	“Perda preferencial de fibras do NA com baixa taxa de disparo espontâneo e alto limiar.”
11	Guest et al.⁽⁵⁾, -2017	Caso controle	● Zumbido
12	Prendergast et al.⁽³²⁾ -2017	Observacional transversal	● SC	“Perda das sinapses entre as CCI e as fibras do NA.”
12	Prendergast et al.⁽³²⁾ -2017	Observacional transversal	● Exposição ao ruído	“Perda das sinapses entre as CCI e as fibras do NA.”
13	Valderrama et al.⁽³³⁾ -2018	Observacional transversal	● SC e PAO - sinônimos	“Teoria conhecida como “PAO”, em que a SC em humanos é a hipótese para explicar déficits de inteligibilidade de fala na presença de audiograma normal.”
13	Valderrama et al.⁽³³⁾ -2018	Observacional transversal	● Exposição ao ruído
14	Guest et al.⁽³⁴⁾ -2018	Observacional transversal	● SC	“Perda de sinapses entre as CCI e as fibras do NA, que pode ocorrer sem perda de células ou elevação permanente do limiar.”
14	Guest et al.⁽³⁴⁾ -2018	Observacional transversal	● Dificuldade de compreensão de fala
15	Bramhall et al.⁽⁶⁾ -2018	Caso controle	● SC	“Dano seletivo das sinapses do nervo auditivo aferente nas CCI, com limiares auditivos dentro dos padrões de normalidade.”
15	Bramhall et al.⁽⁶⁾ -2018	Caso controle	● Exposição ao ruído
16	Guest et al.⁽³⁵⁾ -2019	Observacional transversal	● SC	“Perda de sinapses entre as CCI e as fibras do NA.”
16	Guest et al.⁽³⁵⁾ -2019	Observacional transversal	● Zumbido	“Perda de sinapses entre as CCI e as fibras do NA.”
17	Ridley et al.⁽³⁶⁾ -2019	Caso controle	● SC e PAO - causa/sintoma	“Dano nas FBTE e FMTE do NA, que estão envolvidos no processamento de sons de intensidade moderada a forte e são mais resistentes ao mascaramento por ruído de fundo. Uma possível causa para a PAO é a SC.”
17	Ridley et al.⁽³⁶⁾ -2019	Caso controle	● PASN
18	Grose et al.⁽¹²⁾ -2019	Observacional transversal	● SC	“Dano permanente nas sinapses entre as CCI e as fibras do NA, insuficiente para resultar em uma elevação permanente dos limiares auditivos.”
18	Grose et al.⁽¹²⁾ -2019	Observacional transversal	● Envelhecimento
19	Bhatt and Wang⁽³⁷⁾ -2019	Caso controle	● SC	“Danos irreversíveis nas conexões sinápticas entre as CCI e NA. Esta SC induzida por ruído não pode ser detectada avaliando-se limiares auditivos porque a exposição ao ruído nem sempre causa perda de CCI ou CCE.”
19	Bhatt and Wang⁽³⁷⁾ -2019	Caso controle	● Exposição ao ruído
20	Johannesen et al.⁽³⁸⁾ -2019	Observacional transversal	● SC	“Estudos em animais mostraram que o número de fibras do NA diminui com o aumento da idade de cócleas saudáveis. Alguns autores especulam que a SC e/ou a desaferenciação podem ser responsáveis por dificuldades na compreensão de fala em idosos.”
20	Johannesen et al.⁽³⁸⁾ -2019	Observacional transversal	● Hígidos
21	Risato-Lago et al.⁽³⁹⁾ -2019	Caso controle	● PAO	“Condição na qual o dano do SA não produz mudança de limiar ou há recuperação parcial a medida em que os limites são restaurados aos níveis originais, apesar do dano físico residual.”
21	Risato-Lago et al.⁽³⁹⁾ -2019	Caso controle	● Anemia Falciforme
22	Guest et al.⁽¹⁸⁾ -2019	Caso controle	● SC	“Perda de sinapses entre as CCI da cóclea e fibras do NA, sem perda generalizada de células ciliadas.”
22	Guest et al.⁽¹⁸⁾ -2019	Caso controle	● Hígidos
23	Prendergast et al.⁽⁴⁰⁾ -2019	Observacional transversal	● SC	“Kujawa e Liberman (2009)⁽¹⁾ descreveram o fenômeno hoje conhecido como SC (…)perda de sinapses com limiares absolutos inalterados, mas associada à redução da Onda I.”
23	Prendergast et al.⁽⁴⁰⁾ -2019	Observacional transversal	● Exposição ao ruído
24	Megha et al.⁽⁴¹⁾ -2019	Caso controle	● SC e PAO - sinônimos	“Mudança temporária do limiar, com dano nas conexões entre as fibras do NA e as CCI da cóclea, causando SC. Esse tipo de dano à sinapse, que não causa elevação permanente do limiar, é denominado PAO.”
24	Megha et al.⁽⁴¹⁾ -2019	Caso controle	● Exposição ao ruído
25	Keshishzadeh et al.⁽⁴²⁾ -2020	Caso controle	● SC	“Perda irreversível de sinapses do NA e degeneração de neurônios cocleares, sem lesão das células ciliadas sensoriais cocleares.”
25	Keshishzadeh et al.⁽⁴²⁾ -2020	Caso controle	● Dificuldade de compreensão de fala
26	Mepani et al.⁽⁴³⁾ -2020	Observacional transversal	● SC	“É “oculta” porque a degeneração neural não eleva os limiares comportamentais e eletrofisiológicos até se tornar extrema.”
26	Mepani et al.⁽⁴³⁾ -2020	Observacional transversal	● Hígidos
27	Couth et al.⁽⁴⁴⁾ -2020	Caso controle	● SC e PAO - sinônimos	“Perda de sinapses entre as CCI e os neurônios do gânglio espiral.”
27	Couth et al.⁽⁴⁴⁾ -2020	Caso controle	● Exposição ao ruído
28	Parker et al.⁽¹⁰⁾ -2020	Observacional transversal	● SC e PAO - causa/sintoma	“Perda da conexão sináptica entre as CCI e as fibras do NA, prejudicando a capacidade de compreensão em situações adversas de escuta.”
28	Parker et al.⁽¹⁰⁾ -2020	Observacional transversal	● Hígidos
29	Grant et al.⁽⁹⁾ -2020	Observacional transversal	● SC	“Dano das sinapses entre fibras nervosas cocleares e as e CCI, mesmo quando as células ciliadas e os limiares se recuperam.”
29	Grant et al.⁽⁹⁾ -2020	Observacional transversal	● Hígidos
30	Kara et al.⁽⁴⁵⁾ -2020	Caso controle	● SC e PAO - sinônimos	“Perda das sinapses das CCI sem qualquer evidência de aumento dos limiares auditivos.”
30	Kara et al.⁽⁴⁵⁾ -2020	Caso controle	● Zumbido
31	Bramhall et al.⁽⁸⁾ -2020	Caso controle	● SC	“Perda das conexões sinápticas entre as CCI e seus alvos de fibras nervosas auditivas aferentes.”
31	Bramhall et al.⁽⁸⁾ -2020	Caso controle	● Zumbido e exposição ao ruído
32	Shehorn et al.⁽⁴⁶⁾ -2020	Caso controle	● SC	“Perda de conexões entre as CCI e as fibras nervosas auditivas, na ausência de mudança permanente do limiar.“
32	Shehorn et al.⁽⁴⁶⁾ -2020	Caso controle	● Dificuldade de compreensão de fala
33	Okada et al.⁽⁴⁷⁾, -2020	Observacional transversal	● SC	“Redução na inervação eferente coclear e uma perda de sinapses aferentes entre o NA e as células sensoriais.”
33	Okada et al.⁽⁴⁷⁾, -2020	Observacional transversal	● PAC
34	Washnik et al.⁽⁴⁸⁾ -2020	Caso controle	● SC e PAO - sinônimos	“Danos irreversíveis às conexões sinápticas entre as CCI da cóclea e as fibras do NA. Esse tipo de perda auditiva periférica pode levar à percepção prejudicada da fala e tem sido chamada de “PAO” .”
34	Washnik et al.⁽⁴⁸⁾ -2020	Caso controle	● Exposição ao ruído
35	Carcagno & Plack⁽⁴⁹⁾ -2020	Observacional transversal	● SC	“Perda permanente de sinapses entre as CCI e as fibras do NA.”
35	Carcagno & Plack⁽⁴⁹⁾ -2020	Observacional transversal	● Envelhecimento
36	Marmel et al.⁽⁵⁰⁾ -2020	Caso controle	● SC e PAO - sinônimos	“Patologia auditiva subclínica que poderia explicar algumas dificuldades auditivas observadas apesar dos limiares audiométricos (quase) normais.”
36	Marmel et al.⁽⁵⁰⁾ -2020	Caso controle	● Zumbido
37	Carcagno & Plack⁽⁵¹⁾ -2021	Observacional transversal	● SC	“Perda permanente de sinapses entre as CCI e as fibras do NA.”
37	Carcagno & Plack⁽⁵¹⁾ -2021	Observacional transversal	● Envelhecimento
38	Shim et al.⁽⁵²⁾ -2021	Caso controle	● SC	“A perda seletiva de fibras de alto limiar e/ou sinaptopatia de alto limiar.”
38	Shim et al.⁽⁵²⁾ -2021	Caso controle	● Zumbido unilateral
39	Bal et al.⁽¹¹⁾ -2021	Caso controle	● SC e PAO - sinônimos	“Dano às fibras do nervo coclear, especialmente nas FBTE, com interrupção da comunicação sináptica entre as CCI sensoriais e subconjuntos de fibras do nervo coclear.”
39	Bal et al.⁽¹¹⁾ -2021	Caso controle	● Exposição ao ruído
40	Suresh et al.⁽²⁰⁾ -2021	Caso controle	● SC e PAO - causa/sintoma	“Redução do número de fitas sinápticas entre as CCI e as fibras do NA sem afetar os limiares audiométricos.”
40	Suresh et al.⁽²⁰⁾ -2021	Caso controle	● Exposição ao ruído
41	Nam et al.⁽⁵³⁾ -2021	Caso controle	● SC e PAO - sinônimos	“Quando as sinapses são danificadas, as fibras nervosas posteriormente se degeneram.”
41	Nam et al.⁽⁵³⁾ -2021	Caso controle	● Exposição ao ruído
42	Megha et al.⁽¹³⁾ -2021	Caso controle	● SC e PAO - sinônimos	“Perda de sinapses e terminais nervosos cocleares que inervam as CCI.”
42	Megha et al.⁽¹³⁾ -2021	Caso controle	● Exposição ao ruído e envelhecimento
43	Wang et al.⁽⁷⁾ -2021	Observacional transversal	● SC	“Disfunção permanente nas junções entre as CCI e as fibras do NA causada por trauma de baixo grau na orelha interna, tipicamente associado à exposição ao ruído, insuficiente para elevação permanente dos limiares.”
43	Wang et al.⁽⁷⁾ -2021	Observacional transversal	● Exposição ao ruído
44	Vasilkov et al.⁽⁵⁴⁾ -2021	Caso controle	● SC	“Degeneração dos terminais sinápticos das células ganglionares espirais, que precede o dano das CCI no processo de envelhecimento.”
44	Vasilkov et al.⁽⁵⁴⁾ -2021	Caso controle	● Envelhecimento
45	Bramhall et al.⁽²³⁾ -2021	Caso controle	● SC	“Perda da conexão entre as CCI e seus aferentes alvos de fibra do NA.”
45	Bramhall et al.⁽²³⁾ -2021	Caso controle	● Exposição ao ruído
46	Chen et al.⁽⁵⁵⁾ -2021	Observacional transversal	● SC	“Afeta a conexão entre as CCI, com disfunção nas FBTE, reduzindo a capacidade de percepção da fala em um ambiente ruidoso.”
46	Chen et al.⁽⁵⁵⁾ -2021	Observacional transversal	● Envelhecimento
47	Edvall et al.⁽⁵⁶⁾ -2022	Caso controle	● SC	“Perda da conexão sináptica entre as CCI e as fibras aferentes do NA.”
47	Edvall et al.⁽⁵⁶⁾ -2022	Caso controle	● Zumbido
48	Turner et al.⁽⁵⁷⁾ -2022	Caso controle	● SC	“Alteração sináptica entre as CCI e as fibras nervosas auditivas.”
48	Turner et al.⁽⁵⁷⁾ -2022	Caso controle	● Zumbido
49	Bramhall et al.⁽²⁴⁾ -2022	Caso controle	● SC	“Perda das sinapses entre as CCI e as fibras do nervo auditivo aferente.”
49	Bramhall et al.⁽²⁴⁾ -2022	Caso controle	● Exposição ao ruído

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Legenda: SC = Sinaptopatia Coclear; PAO = Perda Auditiva Oculta; PAC = Processamento Auditivo Central; PASN = Perda Auditiva Sensorioneural; NA = Nervo Auditivo; CCI = Célula Ciliada Interna; FMTE = Fibras de Média Taxa Espontânea; FBTE = Fibras de Baixa Taxa Espontânea; SA = Sistema Auditivo; CCE = Célula Ciliada Externa.

Quanto ao tipo ou desenho de estudo, verificou-se que 31 (63,2/100%) eram do tipo caso-controle e 36,7% (18/49) eram observacionais transversais.

Terminologia utilizada e sua aplicação

Dos 49 artigos selecionados, 61,2% (30/49) utilizaram a terminologia SC para designar o fenômeno que estava pesquisando, 4,1% (02/49) utilizaram apenas o termo PAO e 34,7% (17/49) utilizaram os dois termos.

Dos artigos que adotaram a terminologia SC (estudos 3, 7, 10, 11, 12, 14, 15, 16, 18, 19, 20, 21, 22, 23, 25, 26, 29, 31, 32, 33, 35, 37, 43, 44, 45, 46, 47, 48 e 49), as definições mais utilizadas foram as de Kujawa e Liberman⁽¹⁾, Makary et al.⁽⁵⁸⁾, Sergeyenko et al.⁽⁵⁹⁾ e Liberman e Kujawa⁽⁶⁰⁾. Segundo as definições adotadas nestes artigos, a SC seria a perda de sinapses entre as CCI e as fibras do nervo auditivo, que produz lesões em fibras de baixa taxa de descarga espontânea e alto limiar, na ausência de alteração permanente do limiar auditivo⁽¹⁾. Foi também citada a definição de redução na inervação eferente coclear e a perda de sinapses aferentes entre o nervo coclear e as células sensoriais^(59,60). Estes autores concordam que a SC tem sido evidenciada em estudos com animais, roedores e primatas, principalmente como consequência da exposição a níveis elevados de intensidade sonora^(1,27-29). Devido o comprometimento das sinapses com as fibras eferentes, ocorre comprometimento da codificação do estímulo acústico, uma vez que este inicia o input auditivo no Sistema Auditivo Nervoso Central. Com isto, pode-se inferir que os estudos que utilizaram a terminologia SC de fato objetivaram estudar um fenômeno que se restringe a um local específico de lesão ou mecanismos auditivos. Além disso, não há divergências entre os autores em relação à definição desta^(1,58-60).

O termo PAO isolado foi utilizado pela minoria dos estudos (estudo 1 e 21). Dentre os dois artigos que o adotaram para designar seu objetivo de estudo, um deles o descreveu como uma condição na qual há alteração no sistema auditivo sem que haja mudança no limiar auditivo (estudo 21). Desta forma, os autores consideram a PAO como um sinal de uma doença auditiva e não como a causa em si. No outro artigo (estudo 1) a PAO foi descrita como a desaferenciação entre as fibras do nervo coclear e o GE, em que os limiares auditivos permanecem dentro da normalidade e existe função prejudicada de fibras eferentes que se projetam do tronco encefálico para a cóclea.

Os termos SC e PAO foram adotados em conjunto nos estudos 2,4, 5, 6, 8, 13, 17, 24, 27, 28, 30, 34, 36, 39, 40, 41 e 42. Dos 17 artigos, 76,5% (13/17) assumem a PAO como sinônimo de SC (estudos 2,4, 5, 6, 13, 24, 27, 30, 34, 36, 39, 41 e 42), utilizando as definições de Schaette e colaboradores⁽³⁾, Kuwaja e Liberman⁽¹⁾. Enquanto, 23,5% (04/17) os diferenciam quanto ao fenômeno patológico e o sinal deste (estudos 8, 17, 28 e 40). Em outras palavras, estes autores assumem que uma possível causa para a PAO é a SC.

O termo PAO é utilizado como designação genérica para ao menos 14 doenças que acometem o sistema auditivo e promovem queixa de compreensão de fala no ruído na ausência de perda auditiva periférica. Este termo é amplamente aceito para diferentes descrições fisiopatológicas, desde que não haja alterações no limiar auditivo. Por este motivo, é necessária cautela ao associá-lo como sinônimo da SC, que é caracterizada de forma muito específica, principalmente ao que diz respeito ao seu processo fisiopatológico.

Ainda é necessário acrescentar, que durante a busca dos artigos, em dois dos selecionados, observou-se o uso do termo “transtorno do espectro da neuropatia auditiva” fazendo menção a desaferenciação coclear. A neuropatia auditiva é uma condição bem estabelecida, em que há comprometimento do VIII par craniano, devido a alteração de sincronia neural durante a transmissão sináptica. O local de comprometimento do nervo auditivo é variável e pode haver perda auditiva periférica de diferentes graus, unilateral ou bilateral, simétrica ou não. Desta forma, a neuropatia auditiva é uma condição diferente da SC⁽⁶¹⁾.

População estudada

Os estudos selecionados investigaram diferentes populações e/ou condições. A população exposta a níveis elevados de pressão sonora foi objetivo de pesquisa de 44,8% (22/49) dos estudos, seguida da população com zumbido uni ou bilateral em 24,4% (12/49), 12,2% (06/49) nas condições envelhecimento e 10,2% (05/49) de saúde “hígida”. Perda auditiva condutiva, perda auditiva sensorioneural e Anemia Falciforme representaram 2,0% (01/49) dos estudos. Cabe ressaltar que três artigos estudaram mais de uma condição, dois deles abordaram a exposição a níveis elevados de pressão sonora e zumbido e um artigo as condições de exposição a níveis elevados de pressão sonora e envelhecimento.

A maioria das condições abordadas pelos estudos são apontadas como de risco para a presença da SC (exposição ao ruído, envelhecimento, zumbido). A condição de exposição a níveis elevados de pressão sonora foi a mais estudada (estudos 3, 4, 5, 6, 10, 12, 13, 15, 16, 19, 23, 24, 27, 31, 34, 39, 40, 41, 42, 43, 45, 49), possivelmente por apresentar mecanismos de dano fisiológico conhecidos e relativamente passíveis de controle no que diz respeito ao estudo da SC. E ainda, por ser o fator etiológico mais fundamentado desta patologia. A segunda condição mais investigada foi o zumbido (estudos 1, 7, 8, 9, 11, 13, 30, 31, 36, 38, 47, 48), que também é apontado como um sintoma da SC. Entretanto, algumas considerações quanto a esta condição são necessárias, por se tratar de um sintoma heterogêneo em etiologia, localização, características acústicas, comorbidades associadas, entre outros⁽⁶²⁾. O zumbido frequentemente é associado a perda auditiva, trauma acústico, exposição a níveis elevados de pressão sonora, uso de ototóxicos, alterações cardiovasculares, alteração temporomandibular ou a ausência de causas aparentes⁽³¹⁾. Desta forma, para inferir que o zumbido se deve a SC, outros possíveis fatores devem ser excluídos. Os estudos sobre zumbido incluídos nesta revisão, não referiram excluir ou documentar a presença destas outras condições em sua amostra, com exceção da perda auditiva. O mesmo ocorre para as condições de envelhecimento (estudos 18, 35, 37, 42, 44, 46), de saúde “hígida” (estudos 2, 20, 22, 26, 28, 29) e de queixa de compreensão de fala (14, 25, 32). Para afirmar a presença de SC nestas populações, seria necessária a exclusão das alterações do sistema auditivo nervoso central, pois as mesmas também promovem alterações em habilidades supralimiares⁽⁶³⁾.

As condições de perda auditiva condutiva (estudo 33), perda auditiva sensorioneural (estudo 17) e de Anemia Falciforme (estudo 21), também foram encontradas na busca do presente estudo. O estudo que investigou indivíduos com perda auditiva condutiva utilizou o termo SC. Entretanto, o estudo apenas indicou que a perda auditiva condutiva crônica em adultos pode ser um risco para o desenvolvimento da sinaptopatia coclear. O estudo sobre perda auditiva sensorioneural utilizou os termos SC e PAO como sinônimos e aplicáveis à condição estudada. Entretanto na SC não há alteração de limiar auditivo⁽¹⁾, desta forma, a designação do se investigava pode ter sido equivocada. Por fim, o estudo de indivíduos com Anemia Falciforme utilizou o termo PAO apenas de forma genérica para indicar alterações no sistema auditivo que não promovem alteração no audiograma.

CONCLUSÃO

A terminologia SC foi a mais empregada pelos estudos incluídos, sendo que todos eles faziam referência ao processo fisiopatológico de desaferenciação entre as fibras do nervo coclear e as CCI. A maioria dos estudos que adotou ambos os termos, os utilizou como sinônimo, enquanto os outros estudos descreveram a PAO como sendo uma possível consequência da SC. A menor parte dos estudos utilizou apenas o termo PAO, considerando como um sinal de uma alteração auditiva.

Apêndice 1. Estratégia de busca utilizada de acordo com a base de dados

Base de dados	Estratégia de busca
PUBMED	((“Auditory Synaptopathy”[All Fields] OR ((“neuron s”[All Fields] OR “neuronal”[All Fields] OR “neuronally”[All Fields] OR “neuronals”[All Fields] OR “neurone s”[All Fields] OR “neurones”[All Fields] OR “neuronic”[All Fields] OR “neurons”[MeSH Terms] OR “neurons”[All Fields] OR “neuron”[All Fields] OR “neurone”[All Fields]) AND (“synaptopathies”[All Fields] OR “synaptopathy”[All Fields])) OR “Hidden Hearing Loss”[All Fields]) AND “etiology”[All Fields]) OR “causality”[All Fields] OR “diagnosis”[All Fields].
EMBASE	('auditory synaptopathy'/exp OR 'auditory synaptopathy' OR 'neuronal synaptopathy' OR 'hidden hearing loss'/exp OR 'hidden hearing loss') AND ('etiology'/exp OR 'etiology') OR 'causality'/exp OR 'causality' OR 'diagnosis'/exp OR 'diagnosis'
CINAHL	Auditory Synaptopathy” OR “Neuronal Synaptopathy” OR “Hidden Hearing Loss” AND etiology OR causality OR diagnosis.
Web of Science	“Auditory Synaptopathy” (All Fields) OR “Neuronal Synaptopathy” (All Fields) OR “Hidden Hearing Loss” (All Fields) AND etiology (All Fields) OR causality (All Fields) OR diagnosis (All Fields).

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Footnotes

Trabalho realizado na Pontifícia Universidade Católica de Minas Gerais – PUC MG - Belo Horizonte (MG), Brasil.

Fonte de financiamento: nada a declarar.

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PERMALINK

Cochlear synaptopathy and hidden hearing loss: a scoping review

Marina de Figueiredo Colla

Pamela Papile Lunardelo

Fernanda Abalen Martins Dias

Roles

ABSTRACT

Purpose

Research strategies

Selection criteria

Data analysis

Results

Conclusion

INTRODUCTION

PURPOSE

Search strategy

Selection criteria

Data analysis

RESULTS

Figure 1. Search and selection flowchart.

Characteristics of the studies

Table 1. Characterization of the articles included in the review.

Terminology used and its application

Study Populations

CONCLUSION

Appendix 1. Search strategy used according to the database

Footnotes

REFERENCES

Sinaptopatia coclear e perda auditiva oculta: uma revisão de escopo

Marina de Figueiredo Colla

Pamela Papile Lunardelo

Fernanda Abalen Martins Dias

Roles

RESUMO

Objetivo

Estratégia de pesquisa

Critérios de seleção

Análise dos dados

Resultados

Conclusão

INTRODUÇÃO

OBJETIVO

Estratégia de pesquisa

Critérios de seleção

Análise dos dados

RESULTADOS

Figura 1. Fluxograma de busca e seleção.

Características dos estudos

Tabela 1. Caracterização dos artigos incluídos na revisão.

Terminologia utilizada e sua aplicação

População estudada

CONCLUSÃO

Apêndice 1. Estratégia de busca utilizada de acordo com a base de dados

Footnotes

ACTIONS

PERMALINK

RESOURCES

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